AbbVie's novel Parkinson's drug tavapadon demonstrated significant efficacy in improving motor function across multiple Phase 3 clinical trials, potentially offering a safer alternative to existing therapies with a more convenient dosing schedule.
The TEMPO clinical trial program, presented at the American Academy of Neurology annual meeting in San Diego, evaluated tavapadon—a selective D1/D5 dopamine receptor agonist—in both treatment-naïve patients and those with more advanced disease experiencing motor fluctuations.
Promising Results in Treatment-Naïve Patients
In the TEMPO-1 trial, 529 newly diagnosed, treatment-naïve Parkinson's patients were randomized to receive fixed doses of tavapadon (5 mg or 15 mg) or placebo. After 26 weeks, both dosage groups showed significant improvements in the combined Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III scores.
"The 5 mg dose produced a 9.7-point decrease and the 15 mg dose a 10.2-point decrease, compared to a 1.8-point increase with placebo," reported Dr. Rajesh Pahwa, Laverne and Joyce Rider Professor of Neurology at the University of Kansas School of Medicine. "These benefits started as early as week 4 and were maintained throughout the trial."
Similarly, TEMPO-2 evaluated a flexible dosing regimen (5-15 mg) in 304 treatment-naïve patients. Results showed a 10.3-point reduction in the MDS-UPDRS Parts II and III combined score versus a 1.2-point reduction with placebo.
"A nine-point improvement is nearly unheard of," said Dr. Hubert Fernandez, Director of the Center for Neurological Restoration at Cleveland Clinic's Neurological Institute and global principal investigator for the studies. "This is a really big win for our patients and participants in the clinical trial."
Efficacy as Adjunctive Therapy
For patients with more advanced disease, TEMPO-3 investigated tavapadon as an adjunctive therapy to levodopa. The trial enrolled adults experiencing at least 2.5 hours of "off" time—when symptoms return between levodopa doses—despite taking at least 400 mg of levodopa daily.
Results showed that adding tavapadon increased "on" time without troublesome dyskinesia by 1.1 hours compared to placebo and reduced "off" time by 0.94 hours—meaningful improvements for patients struggling with motor fluctuations.
Differentiated Safety Profile
A key advantage of tavapadon appears to be its safety profile, which researchers attribute to its selective targeting of D1/D5 dopamine receptors rather than the D2/D3 receptors targeted by traditional dopamine agonists.
Across the trials, most adverse events were mild to moderate, with nausea, dizziness, and headache being most common. The incidence of somnolence—excessive daytime sleepiness that has been problematic with D2/D3 agonists—was similar between tavapadon and placebo groups (approximately 3%).
Notably, the incidence of impulse control disorders—compulsive behaviors like gambling, shopping, and hypersexuality that can be devastating side effects of D2/D3 agonists—was low at approximately 1% in the tavapadon groups.
"The safety findings are supportive of a differentiated mechanism of action with tavapadon compared to current D2/D3 receptor-targeting dopamine agonists," Dr. Pahwa noted, though he added that "additional data" would be needed to fully establish this advantage.
Potential Clinical Impact
Tavapadon's once-daily dosing regimen represents another significant advantage over existing therapies, particularly levodopa, which typically requires multiple daily doses.
"Newly diagnosed patients with less severe motor symptoms might be just as satisfied with once-a-day dosing of tavapadon as opposed to a three-times-a-day dosing of levodopa," explained Dr. Fernandez. "Should they require levodopa at some point, they will need a lower dose and less frequency, which then reduces their likelihood of developing motor fluctuations and dyskinesia and other side effects."
For patients already on levodopa, adding tavapadon could help manage motor fluctuations without significantly increasing pill burden. "So regardless of when it's used, whether in the very beginning or as an adjunctive therapy to levodopa, we think it's a gain overall," Dr. Fernandez added.
Historical Context
The development of tavapadon addresses a long-standing challenge in Parkinson's treatment. While levodopa, introduced in the 1960s, remains the most effective therapy for motor symptoms, its long-term use is associated with motor complications like dyskinesia and fluctuations.
Dopamine agonists gained popularity in the 1990s as potential levodopa-sparing agents, but their widespread use has been limited by side effects including sudden sleep attacks and impulse control disorders.
"The challenge was whether we could harness the dopamine-agonist class but not cause D2-related side effects," Dr. Fernandez explained. Tavapadon's selective targeting of D1/D5 receptors, which are more localized to motor neurons, appears to offer a potential solution.
Next Steps
Researchers are currently evaluating the long-term effects of tavapadon in TEMPO-4, an open-label extension trial projected to be completed in January 2026. This study will provide critical data on the drug's safety and efficacy over a 58-week period.
If results continue to be positive, tavapadon could represent a significant advance in Parkinson's disease management, potentially changing treatment paradigms for both newly diagnosed patients and those with advancing disease.
"So far, in the controlled setting of a clinical trial over a three-month period on average for each patient, tavapadon is functioning symptomatically as well as its predecessors, if not a little bit better," Dr. Fernandez concluded. "And it is not causing the idiosyncratic side effects that its predecessors have caused."
